Rényi Entropy-Based Spectrum Sensing in Mobile Cognitive Radio Networks Using Software Defined Radio.
A very important task in Mobile Cognitive Radio Networks (MCRN) is to ensure that the system releases a given frequency when a Primary User (PU) is present, by maintaining the principle to not interfere with its activity within a cognitive radio system. Afterwards, a cognitive protocol must be set in order to change to another frequency channel that is available or shut down the service if there are no free channels to be found. The system must sense the frequency spectrum constantly through the energy detection method which is the most commonly used. However, this analysis takes place in the time domain and signals cannot be easily identified due to changes in modulation, power and distance from mobile users. The proposed system works with Gaussian Minimum Shift Keying (GMSK) and Orthogonal Frequency Division Multiplexing (OFDM) for systems from Global System for Mobile Communication (GSM) to 5G systems, the signals are analyzed in the frequency domain and the Rényi-Entropy method is used as a tool to distinguish the noise and the PU signal without prior knowledge of its features. The main contribution of this research is that uses a Software Defined Radio (SDR) system to implement a MCRN in order to measure the behavior of Primary and Secondary signals in both time and frequency using GNURadio and OpenBTS as software tools to allow a phone call service between two Secondary Users (SU). This allows to extract experimental results that are compared with simulations and theory using Rényi-entropy to detect signals from SU in GMSK and OFDM systems. It is concluded that the Rényi-Entropy detector has a higher performance than the conventional energy detector in the Additive White Gaussian Noise (AWGN) and Rayleigh channels. The system increases the detection probability (PD) to over 96% with a Signal to Noise Ratio (SNR) of 10dB and starting 5 dB below energy sensing levels.


Diabetic distal symmetric polyneuropathy: effect of low-intensity laser therapy.
Low-intensity laser therapy (LILT) has been considered as a treatment modality in diabetic distal symmetric polyneuropathy (DSP). The aim of this study is to determine the effectiveness of LILT on DSP. We examined 107 subjects with type 2 diabetes for detection of DSP using the Michigan Neuropathy Screening Instrument (MNSI). Seventeen subjects were eligible to be enrolled in the study. Nerve conduction studies (NCS) were performed in all eligible subjects as an objective method to confirm neuropathy. The participants received LILT three times a week for ten sessions. NCSs were reevaluated after completion of the treatment. The absolute changes in NCS parameters were considered to establish the effectiveness of the treatment. Baseline demographics were similar in all participants. The mean differences of NCV parameters were considered for comparison. At the end of the study, the subjects showed a significant increase in neural potential amplitudes (p < 0.05). This study clearly demonstrated a significant positive effect of LILT on improvement of nerve conduction velocity on diabetic distal symmetric polyneuropathy (DSP). This finding supports the therapeutic potential of LILT in DSP.


Geometry transformation of ionic surfactants and adsorption behavior on water/n-decane-interface: calculation by molecular dynamics simulation and DFT study.
Understanding the effect of surfactant structure on their ability to modify interfacial properties is of great scientific and industrial interest. In this work, we have synthesized four amide based ionic surfactants under acidic or basic conditions, including CTHA·HCl, CTEA·HCl, CTHA-Na+ and CTEA-Na+. Experiments have proved that the anionic surfactant with polyethylene oxide groups (CTEA-Na+) had the lowest surface tension on the water/n-decane interface. Molecular dynamics simulations have been applied to investigate the structural effect on the adsorption behavior of four different surfactants. The surface tension, interface thickness, interface formation energy, density profiles, order parameters, radial distribution function on the water/n-decane interfaces were calculated and compared. During the equilibrium states, we found that the interface configuration of two cationic surfactants are almost linear while the two anionic surfactants are changed to bending shapes due to the different positions of the hydrophilic head groups. Further DFT study and wavefunction analysis of surfactants have shown that CTEA-Na+ can form stronger vdW interactions with n-decane molecules due to a more neutral electrostatic potential distribution. Meanwhile, the introduction of polyethylene oxide groups has offered more H-bonding sites and resulted in more concentrated H-bonding interactions with water molecules. The difference of weak interactions may contribute to the conformational change and finally affect the interface properties of these ionic surfactants.


Impact of insecticides on parasitoids of the leafminer, Liriomyza trifolii, in pepper in south Texas.
Liriomyza leafminers (Diptera: Agromyzidae) are cosmopolitan, polyphagous pests of horticultural plants and many are resistant to insecticides. Producers in South Texas rely on insecticides as the primary management tool for leafminers, and several compounds are available. The objective of this study is to address the efficacy of these compounds for controlling Liriomyza while minimizing their effects against natural enemies. Research plots were established at Texas AgriLife research center at Weslaco, Texas in fall 2007 and spring 2008 seasons, and peppers were used as a model crop. Plots were sprayed with novaluron, abamectin, spinetoram, lambda-cyhalothrin and water as treatments according to leafminer infestation; insecticide efficacy was monitored by collecting leaves and infested foliage. Plant phenology was also monitored. Novaluron was the most effective insecticide and lambda-cyhalothrin showed resurgence in leafminer density in fall 2007 and no reduction in spring 2008. Other compounds varied in efficacy. Novaluron showed the least number of parasitoids per leafminer larva and the lowest parasitoid diversity index among treatments followed by spinetoram. Liriomyza trifolii (Burgess) was the sole leafminer species on peppers, and 19 parasitoid species were found associated with this leafminer. Application of these insecticides for management of leafminers with conservation of natural enemies is discussed.


MUC4 is negatively regulated through the Wnt/β-catenin pathway via the Notch effector Hath1 in colorectal cancer.
MUC4 is a transmembrane mucin lining the normal colonic epithelium. The aberrant/de novo over-expression of MUC4 is well documented in malignancies of the pancreas, ovary and breast. However, studies have reported the loss of MUC4 expression in the majority of colorectal cancers (CRCs). A MUC4 promoter analysis showed the presence of three putative TCF/LEF sites, implying a possible regulation by the Wnt/β-catenin pathway, which has been shown to drive CRC progression. Thus, the objective of our study was to determine whether MUC4 is regulated by β-catenin in CRC. We first knocked down (KD) β-catenin in three CRC cell lines; LS180, HCT-8 and HCT116, which resulted in increased MUC4 transcript and MUC4 protein. Additionally, the overexpression of stabilized mutant β-catenin in LS180 and HCT-8 resulted in a decrease in MUC4 expression. Immunohistochemistry (IHC) of mouse colon tissue harboring tubular adenomas and high grade dysplasia showed dramatically reduced Muc4 in lesions relative to adjacent normal tissue, with increased cytosolic/nuclear β-catenin. Luciferase assays with the complete MUC4 promoter construct p3778 showed increased MUC4 promoter luciferase activity in the absence of β-catenin (KD). Mutation of all three putative TCF/LEF sites showed that MUC4 promoter luciferase activity was increased relative to the un-mutated promoter. Interestingly, it was observed that MUC4 expressing CRC cell lines also expressed high levels of Hath1, a transcription factor repressed by both active Wnt/β-catenin and Notch signaling. The KD of β-catenin and/or treatment with a Notch γ-secretase inhibitor, Dibenzazepine (DBZ) resulted in increased Hath1 and MUC4 in LS180, HCT-8 and HCT116. Furthermore, overexpression of Hath1 in HCT-8 and LS180 caused increased MUC4 transcript and MUC4 protein. Taken together, our results indicate that the Wnt/β-catenin pathway suppresses the Notch pathway effector Hath1, resulting in reduced MUC4 in CRC.


Calcium-induced inactivation of alamethicin in asymmetric lipid bilayers.
This paper discusses a calcium-dependent inactivation of alamethicin-induced conductance in asymmetric lipid bilayers. The bilayers used were formed with one leaflet of phosphatidyl ethanolamine (PE) and one of phosphatidyl serine (PS). Calcium, initially confined to the neutral lipid (PE) side, can pass through the open alamethicin channel to the negative lipid (PS) side, where it can bind to the negative lipid and reduce the surface potential. Under appropriate circumstances, the voltage-dependent alamethicin conductance is thereby inactivated. We have formulated a model for this process based on the diffusion of calcium in the aqueous phases and we show that the model describes the kinetic properties of the alamethicin conductance under various circumstances. EGTA on the PS side of the membrane reduces the effects of calcium dramatically as predicted by the model.


Neovenatorid theropods are apex predators in the Late Cretaceous of North America.
Allosauroid theropods were a diverse and widespread radiation of Jurassic-Cretaceous megapredators. Achieving some of the largest body sizes among theropod dinosaurs, these colossal hunters dominated terrestrial ecosystems until a faunal turnover redefined apex predator guild occupancy during the final 20 million years of the Cretaceous. Here we describe a giant new species of allosauroid--Siats meekerorum gen. et sp. nov.--providing the first evidence for the cosmopolitan clade Neovenatoridae in North America. Siats is the youngest allosauroid yet discovered from the continent and demonstrates that the clade endured there into the Late Cretaceous. The discovery provides new evidence for ecologic sympatry of large allosauroids and small-bodied tyrannosauroids. These data support the hypothesis that extinction of Allosauroidea in terrestrial ecosystems of North America permitted ecological release of tyrannosauroids, which went on to dominate end-Cretaceous food webs.


History of implantable devices.
The history of biomedical implantable devices is traced from its beginning in the late 1950s to its status today. The role of industry in making this development possible is highlighted. Special emphasis is placed on the early history of the implantable cardiac pacemaker, the first implantable, electronic biomedical device. Implantable drug delivery systems and the implantable defibrillator are also discussed. Implantable devices of the future are briefly described.


Correlation of Brain Perfusion with White Matter Hyperintensity, Brain Atrophy, and Cognition in Patients with Posterior Cerebral Artery Stenosis and Subjective Cognitive Decline.
BACKGROUND This study aimed to investigate the correlation of brain perfusion with white matter hyperintensity (WMH), brain atrophy, and cognition in patients with moderate to severe posterior cerebral artery stenosis (PCAS). MATERIAL AND METHODS 65 patients with memory decline as the main complaint and no history of brain infarction were recruited from the Department of Neurology of Tongji Hospital. Patients with moderate to severe PCAS were included in case group, and subjects with normal intracranial blood vessels served as controls. The demographics and vascular risk factors were recorded. Montreal Cognitive Assessment (MoCA) was used to evaluate the cognition. CT perfusion imaging was performed, and WASID was employed for the assessment of intracranial artery stenosis. The region of interest (ROI) was analyzed based on the whole brain perfusion. Cranial MRI was performed, and Scheltens scoring system was used for the assessment of WMH on FLAIR. T1 weighed images were obtained, and global cortical atrophy (GCA) scale was employed for the assessment of brain atrophy. The detections of brain perfusion, WMH and brain atrophy were done at centrum ovale, parietal lateral ventricle and basal ganglia layers. RESULTS In PCAS patients we found low perfusion in the antecornu and postcornu blood supply areas at the lateral ventricle, the blood supply area of the anterior cerebral artery, the blood supply area of the posterior cerebral artery, and the blood supply area at the hippocampus as compared with control subjects (p<0.05). As compared with control subjects, the incidence of WMH in the blood supply areas at the deep brain and lateral ventricle was significantly higher in PCAS patients (p<0.05). When compared with controls, the incidence of brain atrophy increased significantly in PCAS patients (p<0.01). Correlation analysis showed the brain perfusion at the blood supply area of the posterior cerebral artery was positively correlated to the total MoCA score and negatively correlated to the severity of WMH at the blood supply area of the posterior cerebral artery (p<0.05). Further analysis showed the brain perfusion at the blood supply area of the posterior cerebral artery was negatively associated with cortex supplied by the posterior cerebral artery, posterior cingulate, and hippocampus (p<0.01). CONCLUSIONS PCAS patients have a higher incidence of brain atrophy, and the perfusion at the area supplied by the posterior cerebral artery is correlated to the severity of brain atrophy and of WMH, as well as to cognition decline.


Protection goals for residents in the vicinity of civil airports.
Based on extensive and detailed reviews the present paper suggests evaluation criteria for aircraft noise for the prediction of noise effects and for the protection of residents living in the vicinity of (newly constructed or extended) civil airports. The protection concept provides graded evaluation criteria: Critical loads indicate noise loads that shall be tolerated only exceptionally during a limited time. Protection Guides are central evaluation criteria for taking actions to reduce noise immission. Threshold values inform about measurable physiological and psychological reactions due to noise exposures where long term adverse health effects are not expected. Evaluation criteria are provided for various protection goals, for hearing, communication and sleep, for the avoidance of annoyance and of suspected cardiovascular diseases. As protection of the residents is understood as a dynamic process, these criteria must be repeatedly tested and adapted to new scientific findings.


Cutting edge: expansion of the KIR locus by unequal crossing over.
The killer Ig-like receptor (KIR) genes have high sequence similarity and are organized in a head-to-tail fashion. These properties may enhance misalignment of homologous chromosomes during synapsis preceding meiotic recombination, resulting in unequal crossing over. We have identified an extended KIR haplotype that contains a novel hybrid gene and two copies of each of two previously described KIR genes. A parsimonious mechanism for the derivation of this haplotype invokes unequal crossing over between two known ancestral KIR haplotypes. These data raise the possibility that unequal crossing over may be responsible in part for the expansion/contraction of KIR haplotypes as well as other homologous gene families that map in tandem.


Objectively Measured Physical Activity in Patients with COPD: Recommendations from an International Task Force on Physical Activity.
Physical activity (PA) is of key importance for health among healthy persons and individuals with chronic obstructive pulmonary disease (COPD). PA has multiple dimensions that can be assessed and quantified objectively using activity monitors. Moreover, as shown in the published literature, variable methodologies have been used to date to quantify PA among individuals with COPD, precluding clear comparisons of outcomes across studies. The present paper aims to provide a summary of the available literature for the rationale behind using objectively measured PA and proposes a standardized methodology for assessment, including standard operating procedures for future research. The present paper, therefore, describes the concept of PA, reports on the importance of PA, summarizes the dimensions of PA, provides a standard operating procedure on how to monitor PA using objective assessments, and describes the psychometric properties of objectively measured PA. The present international task force recommends implementation of the standard operating procedure for PA data collection and reporting in the future. This should further clarify the relationship between PA and clinical outcomes, test the impact of treatment interventions on PA in individuals with COPD, and successfully propose a PA endpoint for regulatory qualification in the future.


Relationship between tonsil odor and oral malodor: a clinical study on 48 Iranian patients.
The objective of this study is to evaluate tonsil odor as a contributor to halitosis and to study the reduction of oral malodor by mouth rinsing, without tonsil treatment. In 48 halitosis patients, tonsil odor and oral malodor were assessed through the 0-5 scale. In tonsil odor assessment, a dental burnisher was inserted into the tonsilar crypts and was sniffed by an odor judge. Oral malodor was analyzed through a plastic straw using the same scale by the same judge. The concentrations of H(2)S, CH(3)SH and (CH(3))(2)S were measured by a portable gas chromatograph (GC) (OralChroma) in ppb. After the baseline evaluations the subjects were instructed to scrape the surface of the tongue daily and rinse with a zinc-containing mouthwash twice daily for 1 month. After this period the same evaluations were repeated. Data were analyzed by SPSS software, paired t-test and Pearson correlation. Before mouthwash test: mean values of oral malodor scores and tonsil odor scores were 4.2 and 3.7, respectively. Pearson correlation analysis showed that oral malodor scores and tonsil odor scores had a significant correlation (p = 0.025). Oral malodor scores were correlated with the concentrations of H(2)S (p = 0.0001), CH(3)SH (p = 0.041) but not with (CH(3))(2)S concentration. After mouthwash test: mean values of oral malodor scores and tonsil odor scores were 2.2 and 3.0, respectively. Tonsil odor scores and oral malodor scores were not correlated. Also the paired t-test results showed that the effect of the mouthwash on the reduction of oral malodor and tonsil odor was not the same. Since oral malodor was successfully reduced while tonsil odor remained with a little reduction, it is concluded that tonsilar treatment such as tonsillectomy and laser cryptolysis might be considered only after the failure of mechanochemical therapy.


Morphometric computer-assisted image analysis of epithelial cells in different grades of oral squamous cell carcinoma.
Oral squamous cell carcinoma (OSCC) accounts 94% of all malignant lesions in the oral cavity. In the assessment of OSCC, nowadays the WHO grading system has been followed widely but due to its subjectivity, investigators applied the sophisticated technique of computer-assisted image analysis in the grading of carcinoma in larynx, lungs, esophagus, and cervix to make it more objective. Access, analyze, and compare the cellular area (CA); cytoplasmic area (Cyt A); nuclear area (NA); nuclear perimeter (NP); nuclear form factor (NF); and nuclear-cytoplasmic ratio (N/C) of the cells in different grades of OSCC. Fifty OSCC cases were obtained and stained with hematoxylin and eosin which were graded according to the WHO classification. The sections were subjected to morphometric analysis to analyze all the morphometric parameters in different grades of OSCC and subjected to one-way ANOVA statistical analysis. CA and Cyt A decreased from normal mucosa with dedifferentiation of OSCC. The NA and NP increased in carcinoma group when compared to normal mucosa but decreased with dedifferentiation of OSCC (P < 0.05). NF had no significance with normal mucosa and different grades of OSCC (P > 0.05), while N/C ratio increased from normal mucosa through increasing grades of OSCC, reaching the highest value in poorly differentiated squamous cell carcinoma (P < 0.05). Both cellular and nuclear variables provide a more accurate indication of tumor aggressiveness than any single parameter. Morphometric analysis can be a reliable tool to determine objectively the degree of malignancy at the invasive tumor front.


Unraveling the complexity of neurodegeneration in brains of subjects with Down syndrome: insights from proteomics.
Down syndrome (DS) is one of the most common genetic causes of intellectual disability characterized by multiple pathological phenotypes, among which neurodegeneration is a key feature. The neuropathology of DS is complex and likely results from impaired mitochondrial function, increased oxidative stress, and altered proteostasis. After the age of 40 years, many (most) DS individuals develop a type of dementia that closely resembles that of Alzheimer's disease with deposition of senile plaques and neurofibrillary tangles. A number of studies demonstrated that increased oxidative damage, accumulation of damaged/misfolded protein aggregates, and dysfunction of intracellular degradative systems are critical events in the neurodegenerative processes. This review summarizes the current knowledge that demonstrates a "chronic" condition of oxidative stress in DS pointing to the putative molecular pathways that could contribute to accelerate cognition and memory decline. Proteomics and redox proteomics studies are powerful tools to unravel the complexity of DS phenotypes, by allowing to identifying protein expression changes and oxidative PTMs that are proved to be detrimental for protein function. It is reasonable to suggest that changes in the cellular redox status in DS neurons, early from the fetal period, could provide a fertile environment upon which increased aging favors neurodegeneration. Thus, after a critical age, DS neuropathology can be considered a human model of early Alzheimer's disease and could contribute to understanding the overlapping mechanisms that lead from normal aging to development of dementia.


Melanocyte Response Following Depigmentation by Cryosurgery and Mucosal Excision: A Comparative Clinical and Histopathological Study.
The main aim of this study was to evaluate the melanocyte response following depigmentation by cryosurgery and mucosal excision at both clinical and histopathological levels during 6 months. A total of 15 individuals, aged 25-45 years with hyperpigmentation on the facial aspect of the gingiva present in the esthetic zone were included. A split-mouth approach was used, wherein one side received depigmentation by a scalpel and the other side received cryotherapy, with the choice of the therapy and side chosen by the spin of the coin. For determining the melanocyte assay, a small amount of gingival tissue that was excised was studied under a special staining technique, i.e., Masson-Fontana method for melanin, a histochemistry procedure which determines the activity of melanin both quantitatively and qualitatively. Clinical and histological observations for the intensity of pigmentation were recorded at baseline and 6 months after surgery. Paired and unpaired t-test. Results: The mean value of the Dummett Oral Pigmentation Index (DOPI) was 2.44 ± 0.51 at baseline; following depigmentation with scalpel technique, the mean DOPI was 1.05 ± 0.23 at 6 months; and there was a statistically significant difference in the mean DOPI when compared with that of the baseline (P = 0.001). Following depigmentation with cryosurgery technique, the mean DOPI was 0.33 ± 0.48 at 6 months which also varied statistically significantly with that of the baseline (P = 0.001). The mean value of melanin histopathological count (MHC) was 95.53 ± 9.03 at baseline; following depigmentation with the scalpel technique, the mean DOPI was 89.49 ± 7.56 at 6 months, which was not statistically significant (P = 0.795). Following depigmentation with the cryosurgery technique, the mean MHC was 75.38 ± 5.63 at 6 months, which was not statistically significant (P = 0.285). The mean histologic count of the melanocytes, which accounts for the re-pigmentation process has shown low recurrence values in cryosurgery over the scalpel technique even though the difference was not statistically significant.


Self-medication among nursing workers from public hospitals.
This study describes the prevalence of self-medication and associated factors among nursing workers. This epidemiological sectional study included 1,509 working nurses from two public hospitals in Rio de Janeiro, Brazil. The medications were identified and classified according to the Anatomical Therapeutic Chemical Index. The self-medication prevalence was 24.2% and the most reported anatomical group treated was the nervous system, while the therapeutic group included analgesics. Self-medication was more prevalent among young people, individuals with minor psychiatric disturbances, non-hypertensive individuals, those who did not exercise, those who reported a disease or injury in the last 15 days, with the highest number of self-diagnosed diseases, nurses, professionals with temporary work contracts and those highly involved with their work. Self-medication is a frequent practice among the nursing team members and is associated with factors that should be taken into account when planning strategies aimed at improving workers' health conditions.


Physical characteristics of gastrointestinal content of llama (Lama glama).
Changes in digesta dry matter (DM) and mean digesta particle size (MPS) along the gastrointestinal tract are well known in ruminants, but not in camelids. We collected digesta from the dorsal (d) and ventral (v) first forestomach compartment (C1), the second forestomach compartment (C2), three proximal segments and the subsequent glandular part of the third compartment (C3A-D), the caecum and the faeces twelve llamas (Lama glama). DM analysis indicates the presence of digesta stratification in the C1, the presence of fluid in the C2 to facilitate the sorting function of this compartment, the fluid-absorbing function of the proximal parts of the C3, the secretion of enzymes and digestive acids in the C3D, and the water-resorbing function of the lower intestinal tract. These findings illustrate the functional resemblance between the gastrointestinal tract of camelids and cattle-like ruminants (C1 equivalent to the rumen with stratified contents, C2 to the reticulum, C3A/B/C to the omasum and C3D to the abomasum). MPS analysis revealed a progressive reduction in MPS from the C1 to the distal C3. This gradual transition is different from the clear-cut threshold in ruminants between the reticulum and the omasum and had so far only been described in dromedaries (Camelus dromedarius). These findings indicate that regardless of the convergent property of rumination and resemblance of general mechanisms involved in contents stratification and particle sorting, differences between ruminants and camelids exist that could be interpreted as a more efficient functionality of the ruminant forestomach.


Keto-bridged dual triazole-linked benzenesulfonamides as potent carbonic anhydrase and cathepsin B inhibitors.
Background: Inhibition of human carbonic anhydrase (hCA) isoforms IX and XII with concurrent inhibition of cathepsin B is a promising approach for targeting cancers. Methods/results: 28 keto-bridged dual triazole-containing benzenesulfonamides were synthesized and tested, following the multitarget approach, for their efficacy as inhibitors of cathepsin B and hCA isoforms (I, II, IX, XII). The synthesized compounds showed excellent inhibition of CA isoforms (IX and XII) and cathepsin B. Compound 8i exhibited better and more selective inhibition of the cancer-associated isoform hCA IX as compared with acetazolamide (reference drug) and SLC-0111 (potent lead as carbonic anhydrase inhibitor). Molecular docking studies were also carried out. Conclusion: The present work gives important generalizations for the development of isoform-selective hCA inhibitors endowed with anti-cathepsin properties.


Cell signaling pathways related to pain receptors in the degenerated disk.
Many of the causes of low back pain are still unknown; sufficient evidence indicates that both degenerative and mechanical change within the intervertebral disk (IVD) is a relevant factor. This article reviews intracellular signaling pathways related to pain receptors in the degenerated IVD. Several reports have demonstrated the number of nerve fibers in the IVD was increased in degenerated disks. In recent years, some groups have reported that an increase in nerve fibers is associated with the presence of inflammatory mediators and/or neurotrophins in the IVD. Cell signaling events, which are regulated by inflammatory mediators and neurotrophins, must be identified to clarify the mechanism underlying low back pain. Major intracellular signaling pathways (nuclear factor kappa β, mitogen-activated protein kinases, and Wnts) potentially play vital roles in mediating the molecular events responsible for the initiation and progression of IVD degeneration. These signaling pathways may represent therapeutic targets for the treatment of IVD degeneration and its associated back pain.


Deletion of UCP2 in iNOS deficient mice reduces the severity of the disease during experimental autoimmune encephalomyelitis.
Uncoupling protein 2 is a member of the mitochondrial anion carrier family that is widely expressed in neurons and the immune cells of humans. Deletion of Ucp2 gene in mice pre-activates the immune system leading to higher resistance toward infection and to an increased susceptibility to develop chronic inflammatory diseases as previously exemplified with the Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for multiple sclerosis. Given that oxidative stress is enhanced in Ucp2-/- mice and that nitric oxide (NO) also plays a critical function in redox balance and in chronic inflammation, we generated mice deficient for both Ucp2 and iNos genes and submitted them to EAE. Mice lacking iNos gene exhibited the highest clinical score (3.4+/-0.5 p<0.05). Surprisingly, mice deficient for both genes developed milder disease with reduced immune cell infiltration, cytokines and ROS production as compared to iNos-/- mice.


Chemotaxonomy and cytotoxicity of the liverwort Porella Viridissima.
The first chemotaxonomic study based on volatile components of Porella viridissima (Mitt.) Grolle is reported. The GC-MS analysis of ether extract was performed; ten santalane and five pinguisane-type sesquiterpenes were identified together with perrottetianal A as major diterpene. Most of detected santalane-type sesquiterpenes are reported for the first time in liverwort. P. viridissima was found to belong to the chemotype III (pinguisane/sacculatane) and shared chemical similarities with P. navicularis. Perrotettianal A was isolated and has shown strong cytotoxicity against ovarian cancer.


The occurrence of fatigue in independent and clinically stable filipino patients with idiopathic Parkinson's disease.
Fatigue is a multidimensional problem affecting patients suffering from Parkinson's disease (PD). It is ranked as one of the most bothersome symptom of patients with Parkinson's disease. The study primarily aims to determine the presence of fatigue among clinically stable and independent Filipino patients suffering from idiopathic PD. This study is a prospective cross-sectional study. Recruited patients and control group were all Filipinos. Only independent patients with idiopathic, stable and non-fluctuating PD were included in the study. Those eligible underwent a multitude of screening tests to rule out presence of dementia (Mini Mental Status Examination, MMSE), depression (Montgomery-Åsberg Depression Rating Scale, MADRS), anxiety (Hamilton Anxiety Scale, HAM-A) and sleep disturbance. Disease severity was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and fatigue severity using both the Multicomponent Fatigue Index (MFI) and Fatigue Severity Inventory (FSI). Twenty-eight patients underwent the study. The mean Hoehn and Yahr staging was 1.79. Patients with PD scored higher on both FSI and MFI (individual dimension scores and total score) as compared to the normal controls. The outcome of the study confirmed the presence of fatigue (general, physical, mental), even in clinically stable and independent patients suffering from idiopathic PD, when compared with age-matched healthy controls.


[Family planning as a basic tool for development].
The family planning (FP) concept has traditionally been, and is closely related to, sexual and reproductive health. At the International Conference on Population and Development held in Cairo in 1994, FP is recognized as a health strategy that, properly applied, can contribute to the development of nations. Over the past years we have found that the benefits are not only aimed at preventing unwanted pregnancies, there by preventing induced abortions and maternal death, but it also improves child health, facilitating access to education for children in the world, it promotes the empowerment of women not only in the workplace but also in other areas such as politics and thus, the concept of gender; it helps to reduce poverty by stimulating economic development and increasing the standard of living of people . This means that it not only contributes to one but to the eight Millennium Development Goals by 2015. Despite the evidence of its benefits, there are still social, cultural, political or religious barriers that cause an unmet need in Family Planning, which does not respect the right of individuals to choose and decide the number of children they want, and prevent the experience of a healthy sexuality.


A Bibliometric Analysis and Visualization of Decision Support Systems for Healthcare Referral Strategies.
The referral process is an important research focus because of the potential consequences of delays, especially for patients with serious medical conditions that need immediate care, such as those with metastatic cancer. Thus, a systematic literature review of recent and influential manuscripts is critical to understanding the current methods and future directions in order to improve the referral process. A hybrid bibliometric-structured review was conducted using both quantitative and qualitative methodologies. Searches were conducted of three databases, Web of Science, Scopus, and PubMed, in addition to the references from the eligible papers. The papers were considered to be eligible if they were relevant English articles or reviews that were published from January 2010 to June 2021. The searches were conducted using three groups of keywords, and bibliometric analysis was performed, followed by content analysis. A total of 163 papers that were published in impactful journals between January 2010 and June 2021 were selected. These papers were then reviewed, analyzed, and categorized as follows: descriptive analysis (n = 77), cause and effect (n = 12), interventions (n = 50), and quality management (n = 24). Six future research directions were identified. Minimal attention was given to the study of the primary referral of blood cancer cases versus those with solid cancer types, which is a gap that future studies should address. More research is needed in order to optimize the referral process, specifically for suspected hematological cancer patients.


Loss of Functional Connectivity in Patients with Parkinson Disease and Visual Hallucinations.
Purpose To gain more insight into the pathophysiological mechanisms of visual hallucinations (VHs) in patients with Parkinson disease (PD) by analyzing whole-brain resting-state functional connectivity in PD patients with VH (hereafter, referred to as PD + VH patients) and without VH (hereafter, referred to as PD - VH patients) and control participants. Materials and Methods For this retrospective study, 15 PD + VH patients, 40 PD - VH patients, and 15 control participants from a prospective cohort study were included, which was approved by the local ethics board and written informed consent was obtained from all participants. Functional connectivity was calculated between 47 regions of interests, of which whole-brain and region-specific means were compared by using a general linear model with false discovery rate control for multiple comparisons. Results Whole-brain mean functional connectivity was significantly lower in PD patients compared with control participants, with regional decreases involving paracentral and occipital regions in both PD + VH and PD - VH patients (mean whole-brain functional connectivity in PD + VH vs PD - VH, 0.12 ± 0.01 [standard deviation] vs 0.14 ± 0.03, respectively; control participants, 0.15 ± 0.04; P < .05, corrected). In PD + VH patients, nine additional frontal, temporal, occipital, and striatal regions showed decreased functional connectivity compared with control participants (mean of these nine regions in PD + VH, PD - VH, and control participants: 0.12 ± 0.02, 0.14 ± 0.03, and 0.16 ± 0.04, respectively; P < .05, corrected). Resting-state functional connectivity was unrelated to motor performance (r = 0.182; P = .184) and related to cognitive deficits such as attention and perception (ρ, -0.555 and -0.558, respectively; P < .05). Conclusion The findings show a PD-related effect on resting-state functional connectivity of posterior and paracentral brain regions, whereas the presence of VH is associated with a more global loss of connectivity, related to attention and perception. These findings suggest that the pathophysiological mechanisms of VH in PD may include a global loss of network efficiency, which could drive disturbed attentional and visual processing. © RSNA, 2017 Online supplemental material is available for this article.


Human Adenovirus Serotype 3 Infection Modulates the Biogenesis and Composition of Lung Cell-Derived Extracellular Vesicles.
Adenovirus (Ad) is a major causal agent of acute respiratory infections. However, they are a powerful delivery system for gene therapy and vaccines. Some Ad serotypes antagonize the immune system leading to meningitis, conjunctivitis, gastroenteritis, and/or acute hemorrhagic cystitis. Studies have shown that the release of small, membrane-derived extracellular vesicles (EVs) may offer a mechanism by which viruses can enter cells via receptor-independent entry and how they influence disease pathogenesis and/or host protection considering their existence in almost all bodily fluids. We proposed that Ad3 could alter EV biogenesis, composition, and trafficking and may stimulate various immune responses in vitro. In the present study, we evaluated the impact of in vitro infection with Ad3 vector on EV biogenesis and composition in the human adenocarcinoma lung epithelial cell line A549. Cells were infected in an exosome-free media at different multiplicity of infections (MOIs) and time points. The cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and fluorometric calcein-AM. EVs were isolated via ultracentrifugation. Isolated EV proteins were quantified and evaluated via nanoparticle tracking, transmission electron microscopy, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunoblotting assays. The cell viability significantly decreased with an increase in MOI and incubation time. A significant increase in particle mean sizes, concentrations, and total EV protein content was detected at higher MOIs when compared to uninfected cells (control group). A549 cell-derived EVs revealed the presence of TSG101, tetraspanins CD9 and CD63, and heat shock proteins 70 and 100 with significantly elevated levels of Rab5, 7, and 35 at higher MOIs (300, 750, and 1500) when compared to the controls. Our findings suggested Ad3 could modulate EV biogenesis, composition, and trafficking which could impact infection pathogenesis and disease progression. This study might suggest EVs could be diagnostic and therapeutic advancement to Ad infections and other related viral infections. However, further investigation is warranted to explore the underlying mechanism(s).


Inbred strain differences in prepulse inhibition of the mouse startle response.
Prepulse inhibition is the phenomenon in which a weak prepulse stimulus suppresses the response to a startling stimulus. Patients with schizophrenia have impaired prepulse inhibition which is thought to reflect dysfunctional sensorimotor gating mechanisms. To investigate the potential genetic basis for differences in sensorimotor gating, the responses of 13 inbred strains of mice were evaluated using the prepulse inhibition paradigm. Ten male mice from A/J, AKR/J, BALB/cByJ, BUB/BnJ, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, FVB/NJ, ST/bJ, 129/J, 129/SvJ, 129/SvEvTac inbred strains were tested for acoustic prepulse inhibition of acoustic and tactile startle responses. There was a wide range of responses among the inbred strains of mice. Exact strain distributions were determined for each combination of prepulse sound level and startle stimulus. In general, mice from the 129/SvEvTac, AKR/J, 129/J, and 129/SvJ strains displayed high levels of prepulse inhibition of both the acoustic and tactile startle responses. C57BL/6J, C57BL/10J and BUB/BnJ mice showed low levels of prepulse inhibition. There was also a wide range in the amplitude of the acoustic and tactile startle responses. C57BL/10J and FVB/NJ mice displayed the greatest startle responses and DBA/2J, 129/J and 129/SvJ had the poorest startle responses. There was no correlation between the level of prepulse inhibition and the amplitude of the startle response. These findings indicate that inbred strains of mice may be a useful tool to study the genetic basis of sensorimotor gating.


Thyroid hormone regulation of beta-adrenergic receptor number in aging rats.
To evaluate the capacity of the myocardium in aged rats to respond to hyperthyroidism, we quantified myocardial beta-adrenergic receptors in female Fischer 344 rats of 3, 12, and 24 months of age. In T3-treated rats (500 microgram T3/kg . day for 3 days), myocardial beta-adrenergic receptors, as measured by [3H]dihydroalprenolol binding, were significantly increased (P less than 0.01) over controls in 3-, 12-, and 24-month-old animals. The data demonstrate that senescent rats retain the capacity to increase myocardial beta-adrenergic receptors in response to exogenous hyperthyroidism. In the myocardium, the mechanism of decreased catecholamine responsiveness in aging appears to be at other than the beta-adrenergic receptor site, since receptor density is unaltered with age, as is receptor modulation in response to hyperthyroidism.


Interventions for treating bacterial vaginosis in pregnancy.
Bacterial vaginosis has been associated with poor perinatal outcome. Since the infections are amenable to treatment, identification during pregnancy and treatment may reduce the risk of preterm birth and its consequences. The objective of this review was to assess the effects of antibiotic treatment of bacterial vaginosis in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register. Randomised trials comparing one antibiotic regimen with placebo or no treatment, or which compare two or more alternative antibiotic regimens in pregnant women with bacterial vaginosis. Trial quality assessments and data extraction were done independently by three reviewers. Study authors were contacted for additional information. Five trials involving 1504 women were included. These trials were of good quality. Antibiotic therapy was highly effective at eradicating infection during pregnancy as judged by 'test-of-cure' following therapy (odds ratio 0.22, 95% confidence interval 0.17 to 0.27). The effect of treating bacterial vaginosis during pregnancy showed a trend to less births before 37 weeks gestation (odds ratio 0.78, 95% confidence interval 0.60 to 1.02). The prevention of preterm birth less than 37 weeks gestation was most marked in the subgroup of women with a previous preterm birth (odds ratio 0.37, 95% confidence interval 0.23 to 0. 60). The current evidence does not support screening and treating all pregnant women for bacterial vaginosis to prevent preterm birth and its consequences. For women with a history of a previous preterm birth there is some suggestion that detection and treatment of bacterial vaginosis early in pregnancy may prevent a proportion of these women having a further preterm birth. It is not known whether this is associated with an improvement in neonatal well-being.


Prediction of tuberculosis cases based on sociodemographic and environmental factors in gombak, Selangor, Malaysia: A comparative assessment of multiple linear regression and artificial neural network models.
Early prediction of tuberculosis (TB) cases is very crucial for its prevention and control. This study aims to predict the number of TB cases in Gombak based on sociodemographic and environmental factors. The sociodemographic data of 3325 TB cases from January 2013 to December 2017 in Gombak district were collected from the MyTB web and TB Information System database. Environmental data were obtained from the Department of Environment, Malaysia; Department of Irrigation and Drainage, Malaysia; and Malaysian Metrological Department from July 2012 to December 2017. Multiple linear regression (MLR) and artificial neural network (ANN) were used to develop the prediction model of TB cases. The models that used sociodemographic variables as the input datasets were referred as MLR1 and ANN1, whereas environmental variables were represented as MLR2 and ANN2 and both sociodemographic and environmental variables together were indicated as MLR3 and ANN3. The ANN was found to be superior to MLR with higher adjusted coefficient of determination (R2) values in predicting TB cases; the ranges were from 0.35 to 0.47 compared to 0.07 to 0.14, respectively. The best TB prediction model, that is, ANN3 was derived from nationality, residency, income status, CO, NO2, SO2, PM10, rainfall, temperature, and atmospheric pressure, with the highest adjusted R2 value of 0.47, errors below 6, and accuracies above 96%. It is envisaged that the application of the ANN algorithm based on both sociodemographic and environmental factors may enable a more accurate modeling for predicting TB cases.


A mixed-methods exploration of the contraceptive experiences of female teens with epilepsy.
We explored the contraceptive experiences of female teens with epilepsy, including their knowledge and perceptions of interactions between antiepileptic drugs and hormonal contraception and contraceptive decision-making processes. From November 2012 to May 2013, we conducted one online survey (n=114) and 12 online focus group discussions (n=26) with female teens with epilepsy about their contraceptive experiences and unmet needs. Survey data were analyzed using descriptive statistics and focus group transcripts were analyzed thematically using modified grounded theory methods. Both survey and focus group participants reported believing that interactions between epilepsy medications and hormonal contraceptives could lead to reductions in contraceptive efficacy and seizure control. However, their knowledge about these types of medication interactions was often incomplete. Many study participants viewed contraceptive decision making as a difficult process, and some participants reported avoiding hormonal contraceptives because of potential interactions with antiepileptic drugs. Study participants reported relying on health care providers and parents for contraceptive decision-making support. Focus group participants also reported they wanted health care providers to provide more in-depth and comprehensive counseling about contraception, and that they desired peer support with contraceptive decisions. The ability to make informed contraceptive decisions is important for teens with epilepsy as interactions between anti-epileptic drugs and hormonal contraceptives can impact seizure occurrence and lead to an increased risk of unplanned pregnancy. Guidance for providers offering contraceptive care to this population is needed, as well as a contraceptive support tool that empowers teens with epilepsy to advocate for desired health care.


The phenomenon of acquired resistance to metformin in breast cancer cells: The interaction of growth pathways and estrogen receptor signaling.
Metformin, a biguanide antidiabetic drug, is used to decrease hyperglycemia in patients with type 2 diabetes. Recently, the epidemiological studies revealed the potential of metformin as an anti-tumor drug for several types of cancer, including breast cancer. Anti-tumor metformin action was found to be mediated, at least in part, via activation of adenosine monophosphate-activated protein kinase (AMPK)-intracellular energy sensor, which inhibits the mammalian target of rapamycin (mTOR) and some other signaling pathways. Nevertheless, some patients can be non-sensitive or resistant to metformin action. Here we analyzed the mechanism of the formation of metformin-resistant phenotype in breast cancer cells and its role in estrogen receptor (ER) regulation. The experiments were performed on the ER-positive MCF-7 breast cancer cells and metformin-resistant MCF-7 subline (MCF-7/M) developed due to long-term metformin treatment. The transcriptional activity of NF-κB and ER was measured by the luciferase reporter gene analysis. The protein expression was determined by immunoblotting (Snail1, (phospho)AMPK, (phospho)IκBα, (phospho)mTOR, cyclin D1, (phospho)Akt and ERα) and immunohistochemical analysis (E-cadherin). We have found that: 1) metformin treatment of MCF-7 cells is accompanied with the stimulation of AMPK and inhibition of growth-related proteins including IκBα, NF-κB, cyclin D1 and ERα; 2) long-term metformin treatment lead to the appearance and progression of cross-resistance to metformin and tamoxifen; the resistant cells are characterized with the unaffected AMPK activity, but the irreversible ER suppression and constitutive activation of Akt/Snail1 signaling; 3) Akt/Snail1 signaling is involved into progression of metformin resistance. The results presented may be considered as the first evidence of the progression of cross-resistance to metformin and tamoxifen in breast cancer cells. Importantly, the acquired resistance to both drugs is based on the constitutive activation of Akt/Snail1/E-cadherin signaling that opens new perspectives to overcome the metformin/tamoxifen resistance of breast cancer.


Magnetic resonance imaging and 1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis.
We aimed to increase confidence in the combined use of MRI and proton MR spectroscopy (1H-MRS) in diagnosis of amyotrophic lateral sclerosis (ALS). We investigated 12 patients with ALS, seven definite and five probable, taking into account clinical measures of motor neuron function. On T2-weighted images we found high signal in the corticospinal tract in six and low signal in the primary motor cortex in seven of the 12 patients. Atrophy of the precentral gyrus was apparent in all the patients apart from one with probable ALS. Absolute quantification of cerebral metabolites using 1H-MRS demonstrated a significantly lower mean concentration of N-acetylaspartate (NAA) in the precentral gyrus of patients with probable and definite ALS (8.5 +/- 0.62) than in control subjects (10.4 +/- 0.71; P < 0.001). NAA concentration in primary motor cortex correlated with Norris scale scores (r = 0.30; P < 0.0001) but not with the ALS Functional Rating Scale score or disease duration. Significantly lower levels of NAA were detected in patients with low signal in the motor cortex than in those without (P < 0.01). Mean choline (Cho) and creatine (Cr) values did not differ between patients with ALS and controls.


Large-scale production and purification of functional recombinant bovine rhodopsin with the use of the baculovirus expression system.
Here we describe a generic procedure for the expression and purification of milligram quantities of functional recombinant eukaryotic integral membrane proteins, exemplified by hexahistidine-tagged bovine rhodopsin. These quantities were obtained with the recombinant baculovirus/Sf9 insect cell-based expression system in large-scale bioreactor cultures with the use of a serum-free and protein-free growth medium. After optimization procedures, expression levels up to 4 mg/l were established. The recombinant rhodopsin could be purified with high overall yield by using immobilized-metal-affinity chromatography on Ni(2+)-agarose. After reconstitution into a native lipid environment, the purified protein was functionally indistinguishable from native rhodopsin with regard to the following parameters: spectral absorbance band, structural changes after photoactivation, and G-protein activation. The procedures developed can be adapted to other membrane proteins. The ability to produce and purify tens of milligrams of functional recombinant eukaryotic membrane protein meets the ever-increasing demand of material necessary to perform detailed biochemical and structural biophysical studies that are essential in unravelling their working mechanism at a molecular level.


Economic evaluation of interventions to address undernutrition: a systematic review.
Strategies to address undernutrition in low- and middle-income countries (LMICs) include various interventions implemented through different sectors of the economy. Our aim is to provide an overview of published economic evaluations of such interventions and to compare and contrast evaluations of interventions in different areas. We reviewed economic evaluations of nutrition interventions in LMICs published since 2015 and/or included in the Tufts Global registry or Disease Control Priorities 3rd edition. We categorized the studies by intervention type (preventive; therapeutic; fortification; delivery platforms), nutritional deficiency addressed and characteristics of the economic evaluation (e.g. type of model, costs and outcomes included). Of the 62 economic evaluations identified, 56 (90%) were cost-effectiveness analyses. Twenty-two (36%) evaluations investigated fortification and 23 (37%) preventive interventions. Forty-three percent of the evaluations of preventive interventions did not include a model, whereas most of fortification strategies used the same reference model. We identified different trends in cost categories and inclusion of health and non-health outcomes across evaluations in the four different topic areas. To illustrate the implications of such trends for decision-making, we compared a set of studies evaluating alternative strategies to combat zinc deficiency. We showed that the use of 'off-the-shelf' models and tools can potentially conceal what outcomes and costs and value judgements are used. Comparing interventions across different areas is fundamental to assist decision-makers in developing their nutrition strategy. Systematic differences in the economic evaluations of interventions delivered within and outside the health sector can undermine the ability to prioritize alternative nutrition strategies.


Detection of anovulation by heatmount detectors and transrectal ultrasonography before treatment with progesterone in a timed insemination protocol.
Our objective was to determine the accuracy of identifying noncycling lactating dairy cows before the application of a timed artificial insemination (AI) protocol [with or without progesterone supplementation via a controlled internal drug-release (CIDR) insert and 2 different timings of AI] by using heatmount detectors and a single ovarian ultrasound examination. At 6 locations in the Midwest, 1,072 cows were enrolled in a Presynch protocol (2 injections of PGF(2alpha) 14 d apart), with the second injection administered 14 d before initiating the Ovsynch protocol (injection of GnRH 7 d before and 48 h after PGF(2alpha) injection, with timed AI at 0 or 24 h after the second GnRH injection). Heatmount detectors were applied to cows just before the first Presynch injection, assessed 14 d later at the second Presynch injection (replaced when activated or missing), and reassessed at initiation of the Ovsynch protocol. Ovaries were examined for the presence of a corpus luteum (CL) by ultrasound before the initiation of treatment. Treatments were assigned to cows based on the presence or absence of a CL detected by ultrasound: 1) no CL + no CIDR; 2) no CL + CIDR insert for 7 d; and 3) CL present. Further, alternate cows within the 3 treatments were assigned to be inseminated concurrent with the second GnRH injection of Ovsynch (0 h) or 24 h later. Pregnancy was diagnosed at 33 and 61 d after the second GnRH injection. By using low (<1 ng/mL) concentrations of progesterone in serum as the standard for noncycling status, heatmount detectors were activated on a large percentage of noncycling cows (>60%), whereas the single ultrasound examination incorrectly classified noncycling cows only 21% of the time. Conversely, cycling cows (progesterone > or =1 ng/mL) were correctly identified 70 to 78% of the time by heatmount detectors, but 85 to 92% were correctly identified by ultrasound. Overall accuracy of heatmount detectors and ultrasound was 71 and 84%, respectively. Application of progesterone to cows without a CL at the time of the first injection of GnRH reduced the incidence of ovulation but increased the proportions of pregnancies per AI at d 33 or 61 compared with nontreated cows without a CL at the onset of the Ovsynch protocol. Percentages of cows pregnant and pregnancy survival did not differ for cows having a CL before treatment compared with those not having a CL and treated with progesterone. Compared with no response, when a follicle ovulated in response to the first GnRH injection, percentage of cows becoming pregnant after the timed AI increased from 33.3 to 41.6%. Timing of AI at 0 or 24 h after the second GnRH injection did not alter pregnancies per AI, but cows having luteal activity before treatment had improved pregnancies per AI compared with noncycling cows. We conclude that identifying noncycling cows by ultrasound was more accurate than by heatmount detectors. Subsequent progesterone treatment of previously cycling cows not having a CL at the onset of Ovsynch increased the proportion of pregnant cows, equal to that of cows having a CL but not treated with progesterone.


[Deep cerebral electrical activity during the hypnotic state in man: neurologic considerations in hypnosis].
To the authors' knowledge hypnosis has never been induced in epileptic patients during depth EEG study. This neurosurgical diagnostic procedure (that has been routinely used in medically resistant epileptic patients for the preoperative exact delimitation of the epileptogenic lesion) offers a unique opportunity of obtaining fundamental information on the possible neurophysiological mechanisms implied in human hypnosis. Observations were carried out on 3 consecutive patients affected by medically resistant partial seizures with elementary and/or complex symptomatology. A chronic deep electrode study explored rhinencephalic structures as well as specific target areas of the cerebral cortex. Background electrical activity during the hypnotic state showed a significant decrease of slow waves and an increase of alpha and beta rhythms, with constant increase of amplitude, as compared with the nonhypnotic state. Focal interictal abnormalities were drammatically reduced by hypnotic trance. Moreover, depth EEG study during sleep in one patient indicated that the EEG patterns during hypnosis and sleep are basically different, confirming that there is no convincing evidence of physiological similarities between the 2 states.


Cadmium-induced apoptosis in oyster hemocytes involves disturbance of cellular energy balance but no mitochondrial permeability transition.
Exposure to environmentally prevalent heavy metals such as cadmium can have detrimental effects on a variety of commercially and ecologically important species such as oysters. Since Cd(2+) is known to induce apoptosis in immune cells of vertebrates, we have investigated the effects of this metal on isolated oyster hemocytes, the main cellular immune defense in mollusks. Enhanced apoptosis of these cells could conceivably create immunosuppressed conditions in these organisms and result in reduced disease resistance and increased opportunistic infection, resulting in decline of their populations. Cd(2+) exposure induced apoptosis in oyster hemocytes in a dose-dependent manner in the range of 10-100 micromol l(-1), as indicated by the translocation of phosphatidylserine to the outer leaflet of the plasma membrane. At higher concentrations (200-1000 micromol l(-1)), there was no further increase in apoptosis but a significant increase in the level of necrosis. In stark contrast to vertebrate immune cells, there was no decrease in the mitochondrial membrane potential or activation of caspases in response to Cd(2+) in the apoptotic range. Surprisingly, Cd(2+) exposure in this range did cause a significant decrease in intracellular ATP levels, indicating a severe disturbance of energy metabolism. Similarly, Cd(2+) exposure of isolated mitochondria resulted in partial uncoupling of mitochondria but no difference in mitochondrial membrane potential. The results demonstrate that the important environmental pollutant Cd(2+) induces apoptosis in oyster immune cells and does so through a mitochondria/caspase-independent pathway, suggesting that a novel, perhaps ancient, apoptotic pathway is active in these cells. Furthermore, it appears that the observed decrease in ATP production during apoptosis is not due to the loss of the mitochondrial proton-motive force but is more likely to be due to inhibition of the F(0)/F(1)-ATPase and/or mitochondrial ADP/ATP or substrate transport.


Asymmetric phase masks for extended depth of field.
We present a family of asymmetric phase masks that extends the depth of field of an optical system. To verify our proposal, we compute several modulation transfer functions with focus errors, and we report numerical simulations of the images that can be achieved by use of our proposed procedure.


A mouse Model of Focal Vascular Injury Induces Astrocyte Reactivity, Tau Oligomers, and Aberrant Behavior.
Neuropsychiatric symptom development has become more prevalent with 270,000 blast exposures occurring in the past 10 years in the United States. How blast injury leads to neuropsychiatric symptomology is currently unknown. Preclinical models of blast-induced traumatic brain injury have been used to demonstrate blood-brain barrier disruption, degenerative pathophysiology, and behavioral deficits. Vascular injury is a primary effect of neurotrauma that can trigger secondary injury cascades and neurodegeneration. Here we present data from a novel scaled and clinically relevant mouse blast model that was specifically developed to assess the outcome of vascular injury. We look at the biochemical effects and behavioral changes associated with blast injury in young-adult male BALB/c mice. We report that blast exposure causes focal vascular injury in the Somatosensory Barrel Field cortex, which leads to perivascular astrocyte reactivity, as well as acute aberrant behavior. Biochemical analysis revealed that mild blast exposure also invokes tauopathy, neuroinflammation, and oxidative stress. Overall, we propose our model to be used to evaluate focal blood-brain barrier disruption and to discover novel therapies for human neuropsychiatric symptoms.


Chronic Adrenergic Signaling Causes Abnormal RNA Expression of Proliferative Genes in Fetal Sheep Islets.
Intrauterine growth restriction (IUGR) increases the risk of developing diabetes in later life, which indicates developmental programming of islets. IUGR fetuses with placental insufficiency develop hypoxemia, elevating epinephrine and norepinephrine (NE) concentrations throughout late gestation. To isolate the programming effects of chronically elevated catecholamines, NE was continuously infused into normally grown sheep fetuses for 7 days. High plasma NE concentrations suppress insulin, but after the NE infusion was terminated, persistent hypersecretion of insulin occurred. Our objective was to identify differential gene expression with RNA sequencing (RNAseq) in fetal islets after chronic adrenergic stimulation. After determining the NE-regulated genes, we identified the subset of differentially expressed genes that were common to both islets from NE fetuses and fetuses with IUGR to delineate the adrenergic-induced transcriptional responses. A portion of these genes were investigated in mouse insulinoma (Min6) cells chronically treated with epinephrine to better approximate the β-cell response. In islets from NE fetuses, RNAseq identified 321 differentially expressed genes that were overenriched for metabolic and hormone processes, and the subset of 96 differentially expressed genes common to IUGR islets were overenriched for protein digestion, vitamin metabolism, and cell replication pathways. Thirty-eight of the 96 NE-regulated IUGR genes changed similarly between models with functional enrichment for proliferation. In Min6 cells, chronic epinephrine stimulation slowed proliferation and augmented insulin secretion after treatment. These data establish molecular mechanisms underlying persistent adrenergic stimulation in hyperfunctional fetal islets and identify a subset of genes dysregulated by catecholamines in IUGR islets that may represent programming of β-cell proliferation capacity.


Engineering the Biointerface of Electrospun 3D Scaffolds with Functionalized Polymer Brushes for Enhanced Cell Binding.
Electrospun ultrafine fibers prepared using a blend of poly(lactide- co-glycolide) (PLGA) and bromine terminated poly(l-lactide) (PLA-Br), were surface modified using surface-initiated (SI) Cu(0) mediated polymerization. Copolymers based on N-acryloxysuccinimide (NAS) and a low fouling monomer (either N, N-dimethylacrylamide (DMA), N-(2-hydroxypropyl)acrylamide (HPA), or N-acryloylmorpholine (NAM)) were grafted from the fiber surface to impart surface functionality and to reduce nonspecific protein adsorption. Inclusion of the functional NAS monomer facilitated the conjugation of a nonbioactive cyclic RAD peptide and a bioactive cyclic RGD peptide, the latter expected to facilitate cell adhesion through its affinity for the αvβ3 integrin receptor. A detailed analysis of the surface of the electrospun fiber scaffolds in nongrafted form compared to the surface functionalized state is presented. Characteristic amino acid peaks are observed for both conjugated RGD and RAD peptides. Cell culture experiments confirmed cell specific attachment mediated through the presence of the bioactive RGD peptide mainly at high surface density.


How to make a hippocampal dentate gyrus granule neuron.
Granule neurons in the hippocampal dentate gyrus (DG) receive their primary inputs from the cortex and are known to be continuously generated throughout adult life. Ongoing integration of newborn neurons into the existing hippocampal neural circuitry provides enhanced neuroplasticity, which plays a crucial role in learning and memory; deficits in this process have been associated with cognitive decline under neuropathological conditions. In this Primer, we summarize the developmental principles that regulate the process of DG neurogenesis and discuss recent advances in harnessing these developmental cues to generate DG granule neurons from human pluripotent stem cells.


Visualization of A- and B-genome chromosomes in wheat (Triticum aestivum L.) x jointed goatgrass (Aegilops cylindrica Host) backcross progenies.
Wheat (Triticum aestivum) and jointed goatgrass (Aegilops cylindrica) can cross with each other, and their self-fertile backcross progenies frequently have extra chromosomes and chromosome segments, presumably retained from wheat, raising the possibility that a herbicide resistance gene might transfer from wheat to jointed goatgrass. Genomic in situ hybridization (GISH) was used to clarify the origin of these extra chromosomes. By using T. durum DNA (AABB genome) as a probe and jointed goatgrass DNA (CCDD genome) as blocking DNA, one, two, and three A- or B-genome chromosomes were identified in three BC2S2 individuals where 2n = 29, 30, and 31 chromosomes, respectively. A translocation between wheat and jointed goatgrass chromosomes was also detected in an individual with 30 chromosomes. In pollen mother cells with meiotic configuration of 14 II + 2 I, the two univalents were identified as being retained from the A or B genome of wheat. By using Ae. markgrafii DNA (CC genome) as a probe and wheat DNA (AABBDD genome) as blocking DNA. 14 C-genome chromosomes were visualized in all BC2S2 individuals. The GISH procedure provides a powerful tool to detect the A or B-genome chromatin in a jointed goatgrass background, making it possible to assess the risk of transfer of herbicide resistance genes located on the A or B genome of wheat to jointed goatgrass.


The polo-like kinase Plx1 is required for M phase exit and destruction of mitotic regulators in Xenopus egg extracts.
Polo-like kinases (Plks), named after the Drosophila gene product polo, have been implicated in the regulation of multiple aspects of mitotic progression, including the activation of the Cdc25 phosphatase, bipolar spindle formation and cytokinesis. Genetic analyses performed in yeast and Drosophila suggest a function for Plks at late stages of mitosis, but biochemical data to support such a function in vertebrate organisms are lacking. Here we have taken advantage of Xenopus egg extracts for exploring the function of Plx1, a Xenopus Plk, during the cell cycle transition from M phase to interphase (I phase). We found that the addition of a catalytically inactive Plx1 mutant to M phase-arrested egg extracts blocked their Ca2+-induced release into interphase. Concomitantly, the proteolytic destruction of several targets of the anaphase-promoting complex and the inactivation of the Cdc2 protein kinase (Cdk1) were prevented. Moreover, the M to I phase transition could be abolished by immunodepletion of Plx1, but was restored upon the addition of recombinant Plx1. These results demonstrate that the exit of egg extracts from M phase arrest requires active Plx1, and they strongly suggest an important role for Plx1 in the activation of the proteolytic machinery that controls the exit from mitosis.


Deictic gestures and symbolic gestures produced by adults in an experimental context: hand shapes and hand preferences.
The objective of this study was to gain new insights into the processes underlying gestural communication in adults by examining hand shapes and hand preference patterns associated with different types of gestures. Several communicative situations eliciting pointing gestures and symbolic gestures were presented to 81 participants in an experimental context. Results have highlighted some differences in hand shapes depending on the function of pointing: contrary to results reported in children, the proportion of index-finger gestures was higher in imperative situations than in declarative situations. The distance between the gesturer and the referent was also found to influence hand shapes, proximal pointing being more frequently associated with index-finger gestures than distal pointing. The comparison of hand preferences revealed a greater right-sided asymmetry for declarative pointing than for non-communicative activities, whereas there was no difference between imperative pointing and non-communicative activities, or between symbolic gestures and non-communicative activities. The present study thus sheds some light on the features and the roles of communicative gestures in adults. Results are discussed in relation to the ontogenetic and phylogenetic origins of communication.


Vascular pathology in dermatomyositis and anatomic relations to myopathology.
The causes of perifascicular myofiber atrophy and capillary pathology in dermatomyositis are incompletely understood. We studied 11 dermatomyositis muscles by histochemistry, immunohistochemistry, and ultrastructure. We found that endomysial capillaries within regions of perifascicular atrophy are not entirely lost, but they have reduced size, endothelial loss, C5b9 complement deposits, and relatively preserved connective tissue molecules and pericytes. In all muscles, the perimysium varies regionally. Some areas contain intermediate-sized vessels. Others are avascular. In dermatomyositis, vascular perimysium contains abnormal vessel fragments, perivascular inflammation, and increased PECAM-1. Perifascicular myofiber atrophy and capillary pathology are concentrated near the avascular perimysium. We conclude that both perimysial intermediate-sized vessels and endomysial capillaries within regions of perifascicular myofiber atrophy are abnormal in dermatomyositis. Capillary damage and myofiber atrophy are concentrated in regions distant from intermediate-sized perimysial vessels. Chronic immune vascular damage and insufficiency in dermatomyositis may cause ischemia, myofiber atrophy, and capillary damage in "watershed" regions of muscle near the avascular perimysium.


Revision of the Genus Crioprosopus Audinet-Serville, and description of three new genera of Trachyderini (Coleoptera: Cerambycidae: Cerambycinae).
The genera Callona Waterhouse, 1840 and Crioprosopus Audinet-Serville, 1834 (Coleoptera: Cerambycidae: Cerambycinae: Trachyderini) are revised. The genus Callona is synonymized with Crioprosopus, and new genera, Callistochroma gen. nov., Megapurpuricenus gen. nov. and Pilostenaspis gen. nov. are described. Five species, three previously included in Callona [C. flavofasciata Chemsak & Hovore, 2011, lampros (Bates, 1885), and rutilans (Bates 1869)], and two from Crioprosopus [C. cacicus (Bates, 1885) and viridipennis (Latreille, 1811)], are transferred to Callistochroma, with viridipennis designated as the type species. Two species, one previously described as Crioprosopus (C. lateralis LeConte, 1884) and another from Stenaspis Audinet-Serville (S. pilosella Bates, 1892), are transferred into Pilostenaspis, with lateralis designated as the type species. Crioprosopus magnificus (LeConte, 1875) is transferred into Megapurpuricenus, and designated as the type species. Keys to the above genera and species along with illustrations of the available species in color are included. New species described include: Pilostenaspis copei sp. nov. from Mexico; Crioprosopus wappesi sp. nov. from Guatemala; Crioprosopus hondurensis sp. nov. from Honduras; Callistochroma chrysiptera sp. nov. and Crioprosopus chiriquiensis sp. nov. from Panama, and Callistochroma viridipurpurea sp. nov. from Colombia.


Long noncoding RNA TMEM147-AS1 serves as a microRNA-326 sponge to aggravate the malignancy of gastric cancer by upregulating SMAD5.
The abnormal expression of long noncoding RNAs (lncRNAs) is frequently observed in gastric cancer (GC) and considered an important driving force in GC progression. However, little is known regarding the involvement of TMEM147-AS1 in GC. Therefore, we examined TMEM147-AS1 expression in GC and determined its prognostic value. In addition, TMEM147-AS1 expression was depleted to identify the functional changes in response to TMEM147-AS1 deficiency. Using the cancer genome atlas dataset and our own cohort, we identified a strong expression of TMEM147-AS1 in GC. Increased TMEM147-AS1 levels in GC showed a significant association with poor prognosis. TMEM147-AS1 interference resulted in the inhibition of GC cell proliferation, colony-forming, migration, and invasion in vitro. Additionally, depletion of TMEM147-AS1 restricted the growth of GC cells in vivo. Mechanistically, TMEM147-AS1 functioned as a microRNA-326 (miR-326) sponge. Furthermore, SMAD family member 5 (SMAD5) was experimentally validated as the functional effector of miR-326. TMEM147-AS1 was demonstrated to sequester miR-326 away from SMAD5; consequently, knocking down TMEM147-AS1 downregulated SMAD5 levels in GC cells. The functional suppression of miR-326 or reintroduction of SMAD5 effectively reversed the attenuated behavior of GC cells caused by TMEM147-AS1 downregulation. In summary, TMEM147-AS1 exhibits tumorigenic activities in GC, which is likely the result of an altered miR-326/SMAD5 axis. Therefore, targeting TMEM147-AS1/miR-326/SMAD5 may represent a target for the treatment of GC.


PBP2a mutations causing high-level Ceftaroline resistance in clinical methicillin-resistant Staphylococcus aureus isolates.
Ceftaroline is the first member of a novel class of cephalosporins approved for use in the United States. Although prior studies have identified eight ceftaroline-resistant methicillin-resistant Staphylococcus aureus (MRSA) isolates in Europe and Asia with MICs ranging from 4 to 8 mg/liter, high-level resistance to ceftaroline (>32 mg/liter) has not been described in MRSA strains isolated in the United States. We isolated a ceftaroline-resistant (MIC > 32 mg/liter) MRSA strain from the blood of a cystic fibrosis patient and five MRSA strains from the respiratory tract of this patient. Whole-genome sequencing identified two amino acid-altering mutations uniquely present in the ceftaroline-binding pocket of the transpeptidase region of penicillin-binding protein 2a (PBP2a) in ceftaroline-resistant isolates. Biochemical analyses and the study of isogenic mutant strains confirmed that these changes caused ceftaroline resistance. Thus, we identified the molecular mechanism of ceftaroline resistance in the first MRSA strain with high-level ceftaroline resistance isolated in the United States.


Donepezil provides positive effects to patients treated with gabapentin for neuropathic pain: an exploratory study.
The first-line medication gabapentin and the acetylcholinesterase inhibitor donepezil represent a new promising combination to improve treatment outcomes for patients with severe neuropathic pain. The drugs have previously shown synergism following co-administration in nerve-injured rats. The clinical relevance of adding donepezil to existing gabapentin treatment in patients with post-traumatic neuropathic pain was explored in this open-label study. The study comprised two consecutive periods of minimum 6 weeks: (1) titration of gabapentin to the highest tolerable dose or maximum 2400 mg daily, and (2) addition of donepezil 5 mg once daily to the fixed gabapentin dose. Efficacy and tolerability were assessed by ratings of pain intensity, questionnaires for pain and health-related quality of life, and reporting of adverse events. Pain scores were also analysed using mixed-effects analysis with the software NONMEM to account for intersubject variability. Eight patients commenced treatment with donepezil, of which two withdrew because of adverse events. Addition of donepezil resulted in clinically relevant reductions of pain (> 11 units on a 0-100 scale) and improved mental wellness in three of six patients. The remaining three patients had no obvious supplemental effect. Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (P < 0.0001 combination vs. monotherapy). Donepezil may provide additional analgesia to neuropathic pain patients with insufficient pain relief from gabapentin as monotherapy. The promising results support controlled clinical trials of the drug combination. The usefulness of mixed-effects analysis in small-scale trials and/or for data with high intersubject variability was also demonstrated.


Relative contributions of Pseudomonas aeruginosa ExoU, ExoS, and ExoT to virulence in the lung.
Pseudomonas aeruginosa uses a type III secretion system to promote development of severe disease, particularly in patients with impaired immune defenses. While the biochemical and enzymatic functions of ExoU, ExoS, and ExoT, three effector proteins secreted by this system, are well defined, the relative roles of each protein in the pathogenesis of acute infections is not clearly understood. Since ExoU and ExoS are usually not secreted by the same strain, it has been difficult to directly compare the effects of these proteins during infection. In the work described here, several isogenic mutants of a bacterial strain that naturally secretes ExoU, ExoS, and ExoT were generated to carefully evaluate the relative contribution of each effector protein to pathogenesis in a mouse model of acute pneumonia. Measurements of mortality, bacterial persistence in the lung, and dissemination indicated that secretion of ExoU had the greatest impact on virulence while secretion of ExoS had an intermediate effect and ExoT had a minor effect. It is of note that these results conclusively show for the first time that ExoS is a virulence factor. Infection with isogenic mutants secreting wild-type ExoS, ExoS defective in GTPase-activating protein (GAP) activity, or ExoS defective in ADP-ribosyltransferase activity demonstrated that the virulence of ExoS was largely dependent on its ADP-ribosyltransferase activity. The GAP activity of this protein had only a minor effect in vivo. The relative virulence associated with each of these type III effector proteins may have important prognostic implications for patients infected with P. aeruginosa.


Effects of sleep on spinal nociceptive reflexes in humans.
Controversy continues to surround the monosynaptic and polysynaptic spinal reflexes during the different stages of sleep. In animal studies both of these reflexes were found to be depressed during desynchronized sleep. In humans, the H reflex was unchanged whereas the second component of the nociceptive flexion reflex was increased. However, abolition of the H reflex and F waves during REM sleep has also been reported. The aim of this investigation was to examine the effects of different sleep stages on the polysynaptic nociceptive flexion reflex. Six healthy volunteers were studied. The RIII reflex was studied according to Willer's method (1977) during the different stages of NREM and REM sleep. The RIII reflex threshold was found to increase during stage 2 of NREM sleep. It remained higher during stages 3 and 4. During REM sleep a further increase in the reflex threshold was observed. The reflex latency was prolonged during stage 4 of NREM sleep. There was evidence of further latency prolongation during REM sleep. It was also during REM sleep that the maximum increase in the amplitude and duration of the reflex were recorded.


Weight loss from 20 years of age is associated with cognitive impairment in middle-aged and elderly individuals.
Few empirical studies have been conducted to identify modifiable factors that may affect cognitive impairment in Japanese individuals. The present study aimed to clarify whether body mass and lifestyle are associated with cognitive impairment in Japanese middle-aged and elderly individuals. Subjects were 1814 community-dwelling individuals aged 44-79 years, all of whom were participants of the Murakami Cohort Study baseline survey conducted in 2011-2013. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) in 2014-2016, and cognitive impairment, the outcome measure, was defined as an MMSE score <24. Predictor variables were body mass index (BMI), long-term weight changes from 20 years of age, and lifestyle factors, such as smoking, drinking, and physical activity levels, which were obtained from a self-administered questionnaire in the baseline survey. Covariates were sex, age, education level, and histories of stroke and diabetes. Multiple logistic regression analysis was used to calculate the adjusted odds ratios (ORs). The prevalence of overall cognitive impairment was 6.2%. The adjusted ORs of cognitive impairment in the lowest (<[-4]kg) (OR = 2.70, 95%CI, 1.18-6.20) and second ([-4]-[0]kg) (OR = 2.37, 95%CI, 1.04-5.37) quintiles for long-term weight change were significantly higher than the reference 4th quintile ([+4]-[+7]kg). The adjusted OR in the highest quintile (≥[+8]kg) was 2.24 (95%CI, 0.99-5.04). Current BMI was not associated with cognitive impairment. Long-term weight loss is associated with cognitive impairment in Japanese middle-aged and elderly individuals. Because the present study was retrospective in nature, prospective studies should also be conducted for further characterization of this association.


Comparison of neural activity preceding reaches to auditory and visual stimuli in the parietal reach region.
We examined the responses of neurons in the parietal reach region (PRR) during reaches to the remembered locations of auditory or visual stimuli. We found that the firing rate of PRR neurons contained information about the location of auditory and visual stimuli. For neurons tested with visual stimuli, the amount of information remained constant throughout the task. In contrast, for neurons tested with auditory stimuli, the amount of target-location information increased as the trial evolved. During the reach period of the task, the amount of information that was carried by neurons tested with auditory stimuli was not statistically different from the amount carried by neurons tested with visual stimuli. We interpret these data to suggest that the type of information that PRR neurons encode evolves throughout a task.


Postnatal apoptosis, development, and sex difference in the lateral septum of rats.
To determine whether apoptosis is involved in the formation of the structure and morphological sex difference of the lateral septum (LS), the postnatal developmental changes in the number of apoptotic cells were examined in the LS on postnatal day 1 (PD1 = birth day), 4, 6, 8, 11, 16, and 31 in male and female rats. Apoptotic cells were immunohistochemically detected by antibody against single-stranded DNA (ssDNA) or active caspase-3. The volume of the LS was also measured and was found to increase with age. The number of apoptotic cells detected by anti-ssDNA in the LS increased from PD1 to PD8 but decreased after PD11. Also, the LS was divided into dorsal, intermediate, and ventral parts (LSd, LSi, and LSv), and the volume and number of ssDNA-immunoreactive cells in each part were measured on PD6, 8, 11, 16, and 31. In both sexes, a large number of ssDNA-immunoreactive cells was found in the LSd and LSi on PD8 (but not on PD6) and in the LSv on PD6 and PD8. On PD6, the number of active caspase-3-immunoreactive cells was significantly greater in the LSv than in the LSd or LSi, in both sexes. Only the LSi of males had a high number of ssDNA-immunoreacitve cells on PD16; the number was significantly greater than that of females of the same age. However, there was no significant sex difference in the number of active caspase-3-immunoreacitve cells in the LSi on PD16. On PD31, the volume of the LSi was significantly greater in females than in males. There was no sex difference in volume or number of apoptotic cells in the LSd or LSv. These findings indicate that loss of cells due to apoptosis, which is partially caused by activation of caspase-3, occurs in the LS during postnatal development, with regional differences. They also indicate that sex difference in caspase-3-independent apoptosis contributes to morphological sexual differentiation of the LSi.


Clinical Features Observed in General Practice Associated With the Subsequent Diagnosis of Progressive Supranuclear Palsy.
Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder that is difficult for primary care physicians to recognize due to its progressive nature and similarities to other neurologic disorders. This case-control study aimed to identify clinical features observed in general practice associated with a subsequent diagnosis of PSP. Methods: We analyzed a de-identified dataset of 152 PSP cases and 3,122 matched controls from electronic medical records of general practices in Germany. We used a random forests algorithm based on machine learning techniques to identify clinical features (medical conditions and treatments received) associated with pre-diagnostic PSP without using an a priori hypothesis. We then assessed the relative effects of the features with the highest importance scores and generated multivariate models using clustered logistic regression analyses to identify a subset of clinical features associated with subsequent PSP diagnosis. Results: Using the random forests approach, we identified 21 clinical features associated with pre-diagnostic PSP (odds ratio ≥2.0 in univariate analyses). From these, we constructed a multivariate model comprising 9 clinical features with ~90% likelihood of identifying a subsequent PSP diagnosis. These features included known PSP symptoms, common misdiagnoses, and 2 novel associations, diabetes mellitus and cerebrovascular disease, which are possible modifiable risk factors for PSP. Conclusion: In this case-control study using data from electronic medical records, we identified 9 clinical features, including 2 previously unknown factors, associated with the pre-diagnostic stage of PSP. These may be used to facilitate recognition of PSP and reduce time to referral by primary care physicians.


Use of isotope dilution method to predict bioavailability of organic pollutants in historically contaminated sediments.
Many cases of severe environmental contamination arise from historical episodes, where recalcitrant contaminants have resided in the environment for a prolonged time, leading to potentially decreased bioavailability. Use of bioavailable concentrations over bulk chemical levels improves risk assessment and may play a critical role in determining the need for remediation or assessing the effectiveness of risk mitigation operations. In this study, we applied the principle of isotope dilution to quantify bioaccessibility of legacy contaminants DDT and PCBs in marine sediments from a Superfund site. After addition of 13C or deuterated analogues to a sediment sample, the isotope dilution reached a steady state within 24 h of mixing. At the steady state, the accessible fraction (E) derived by the isotope dilution method (IDM) ranged from 0.28 to 0.89 and was substantially smaller than 1 for most compounds, indicating reduced availability of the extensively aged residues. A strong linear relationship (R2=0.86) was found between E and the sum of rapid (Fr) and slow (Fs) desorption fractions determined by sequential Tenax desorption. The IDM-derived accessible concentration (Ce) was further shown to correlate closely with tissue residue in the marine benthic polychaete Neanthes arenaceodentata exposed in the same sediments. As shown in this study, the IDM approach involves only a few simple steps and may be readily adopted in laboratories equipped with mass spectrometers. This novel method is expected to be especially useful for historically contaminated sediments or soils, for which contaminant bioavailability may have changed significantly due to aging and other sequestration processes.


Synthesis of C-Glucosylated Octaketide Anthraquinones in Nicotiana benthamiana by Using a Multispecies-Based Biosynthetic Pathway.
Carminic acid is a C-glucosylated octaketide anthraquinone and the main constituent of the natural dye carmine (E120), possessing unique coloring, stability, and solubility properties. Despite being used since ancient times, longstanding efforts to elucidate its route of biosynthesis have been unsuccessful. Herein, a novel combination of enzymes derived from a plant (Aloe arborescens, Aa), a bacterium (Streptomyces sp. R1128, St), and an insect (Dactylopius coccus, Dc) that allows for the biosynthesis of the C-glucosylated anthraquinone, dcII, a precursor for carminic acid, is reported. The pathway, which consists of AaOKS, StZhuI, StZhuJ, and DcUGT2, presents an alternative biosynthetic approach for the production of polyketides by using a type III polyketide synthase (PKS) and tailoring enzymes originating from a type II PKS system. The current study showcases the power of using transient expression in Nicotiana benthamiana for efficient and rapid identification of functional biosynthetic pathways, including both soluble and membrane-bound enzymes.


Evidence for the use of probiotics and prebiotics in inflammatory bowel disease: a review of clinical trials.
Human subjects and their enteric microbiota have evolved together to reach a state of mutual tolerance. Mounting evidence from both animal models and human studies suggests that inflammatory bowel disease (IBD) represents a malfunction of this relationship. The enteric microecology therefore represents an attractive therapeutic target with few side effects. Probiotics and prebiotics have been investigated in clinical trials as treatments for IBD, with conflicting results. The evidence for the use of probiotics in the management of pouchitis is persuasive and several studies indicate their effectiveness in ulcerative colitis. Trials of probiotics and prebiotics in Crohn's disease are less convincing. However, methodologies vary widely and a range of probiotic, prebiotic and combination (synbiotic) treatments have been tested in a variety of patient groups with an assortment of end points. Conclusions about any one treatment in a specific patient group can therefore only be drawn on evidence from relatively small numbers of patients. The present article reviews the role of the intestinal microbiota in the pathogenesis of IBD and addresses the clinical evidence for the therapeutic manipulation of bowel microbiota using probiotics, prebiotics and synbiotics in IBD.


A natural vanishing act: the enzyme-catalyzed degradation of carbon nanomaterials.
Over the past three decades, revolutionary research in nanotechnology by the scientific, medical, and engineering communities has yielded a treasure trove of discoveries with diverse applications that promise to benefit humanity. With their unique electronic and mechanical properties, carbon nanomaterials (CNMs) represent a prime example of the promise of nanotechnology with applications in areas that include electronics, fuel cells, composites, and nanomedicine. Because of toxicological issues associated with CNMs, however, their full commercial potential may not be achieved. The ex vitro, in vitro, and in vivo data presented in this Account provide fundamental insights into the biopersistence of CNMs, such as carbon nanotubes and graphene, and their oxidation/biodegradation processes as catalyzed by peroxidase enzymes. We also communicate our current understanding of the mechanism for the enzymatic oxidation and biodegradation. Finally, we outline potential future directions that could enhance our mechanistic understanding of the CNM oxidation and biodegradation and could yield benefits in terms of human health and environmental safety. The conclusions presented in this Account may catalyze a rational rethinking of CNM incorporation in diverse applications. For example, armed with an understanding of how and why CNMs undergo enzyme-catalyzed oxidation and biodegradation, researchers can tailor the structure of CNMs to either promote or inhibit these processes. In nanomedical applications such as drug delivery, the incorporation of carboxylate functional groups could facilitate biodegradation of the nanomaterial after delivery of the cargo. On the other hand, in the construction of aircraft, a CNM composite should be stable to oxidizing conditions in the environment. Therefore, pristine, inert CNMs would be ideal for this application. Finally, the incorporation of CNMs with defect sites in consumer goods could provide a facile mechanism that promotes the degradation of these materials once these products reach landfills.


Impact of anti-thymocyte globulin during immunosuppression induction in patients with hepatitis C after liver transplantation.
Induction immunosuppression with anti-thymocyte globulin (ATG) provides potential benefits after liver transplantation (LT). However, its use in patients with LT and hepatitis C (HCV) is controversial. To evaluate the 1- and 2-year patient survival and HCV recurrence rate in patients receiving ATG during the induction phase of immunosuppression (IPI) after LT. A total of 49 patients undergoing their first LT for HCV were randomized to receive ATG during IPI. Patient survival and HCV recurrence were determined at 1 and 2 years. The frequency of acute cellular rejection (ACR), infections, and neoplasms was also evaluated. Twenty-six patients were randomized to receive ATG (Arm-1) and 23 to standard induction therapy (Arm-2). Those given ATG had lower HCV recurrence (26.9 vs 73.9 %, p = 0.001). The 1- and 2-year patient survival rates were similar for both arms (p = 0.33). Infections occurred in 46.1 % subjects in Arm-1 and 34.7 % in Arm-2 (p = 0.562). There was a greater proportion of fungal infections in Arm-1 (19.2 vs 0 %, p = 0.032). ATG during the IPI was associated with lower frequency of recurrence of HCV in patients undergoing LT. This, however, did not affect the 1- and 2-year survival and the frequency of ACR, infections, or neoplasms.


A neuromorphic depth-from-motion vision model with STDP adaptation.
We propose a simplified depth-from-motion vision model based on leaky integrate-and-fire (LIF) neurons for edge detection and two-dimensional depth recovery. In the model, every LIF neuron is able to detect the irradiance edges passing through its receptive field in an optical flow field, and respond to the detection by firing a spike when the neuron's firing criterion is satisfied. If a neuron fires a spike, the time-of-travel of the spike-associated edge is transferred as the prediction information to the next synapse-linked neuron to determine its state. Correlations between input spikes and their timing thus encode depth in the visual field. The adaptation of synapses mediated by spike-timing-dependent plasticity is used to improve the algorithm's robustness against inaccuracy caused by spurious edge propagation. The algorithm is characterized on both artificial and real image sequences. The implementation of the algorithm in analog very large scale integrated (aVLSI) circuitry is also discussed.